Effects of an elemental diet to reduce adverse events in patients with esophageal cancer receiving docetaxel/cisplatin/5-fluorouracil: a phase III randomized controlled trial-EPOC 2 (JFMC49-1601-C5).

BACKGROUND: Oral mucositis (OM) is an unpleasant adverse event in patients receiving chemotherapy. A prospective feasibility study showed that elemental diet (ED), an oral supplement that does not require digestion, may prevent OM. Based on this, we established a central review system for oral cavity assessment by dental oncology specialists blinded to background data. We used this system to elucidate the preventive effect of an ED against OM in patients with esophageal cancer receiving docetaxel, cisplatin, and 5-fluorouracil (DCF) therapy. PATIENTS AND METHODS: In this phase III, multicenter, parallel-group, controlled trial, patients consuming a normal diet orally were randomly assigned (1 : 1) to receive two cycles of DCF with (group A) or without (group B) an ED (Elental® 160 g/day). We assessed the incidence of grade ≥2 OM evaluated by two reviewers, changes in body weight, prealbumin, C-reactive protein, and DCF completion rate based on ED compliance. RESULTS: Of the 117 patients randomly assigned to treatment, four failed to start treatment and were excluded from the primary analysis; thus, groups A and B comprised 55 and 58 patients, respectively. There were no significant differences in background characteristics. Grade ≥2 OM was observed in eight (15%) and 20 (34%) patients in groups A and B, respectively (P = 0.0141). Changes in body weight and prealbumin during the two DCF cycles were significantly higher in group A than B (P = 0.0022 and 0.0203, respectively). During the first cycle, changes in C-reactive protein were significantly lower in group A than B (P = 0.0338). In group A (receiving ED), the DCF completion rate was 100% in patients with 100% ED compliance and 70% in patients failing ED completion (P = 0.0046). CONCLUSIONS: The study findings demonstrate that an ED can prevent OM in patients with esophageal cancer receiving chemotherapy.

Low-dose hyperthermia enhances the antitumor effects of chemotherapy in squamous cell carcinoma.

Esophageal squamous cell carcinoma is a highly aggressive neoplasm and the sixth leading cause of global cancer-related death; the 5-year survival rate for esophageal cancer is only about 20%-25% for all stages. Therefore, improving the therapeutic effect is important. This study assessed whether low-dose hyperthermia (LDH) enhances the antitumor effects of chemotherapy. The antitumor effect of chemotherapy with/without LDH in the squamous cell carcinoma cell line SCCVII was evaluated. A comprehensive analysis was performed with real-time polymerase chain reaction (PCR) to study the hyperthermia-induced changes in the gene expression of SCCVII cell lines. In addition, the cytotoxic and apoptotic changes in the cells treated with LDH combined with/without 5-fluorouracil (5-FU) were measured. LDH combined with 5-FU (10 nM) strongly inhibited the cell growth of SCCVII, with flow cytometry showing an increased population of apoptotic cells. PCR showed that LDH promoted a 25.22-fold increase of p53 mRNA and 18.08-fold increase of Bax mRNA in vitro. MDR1 expression was decreased to 28.7% after LDH. This treatment can result in much higher efficacy of antitumor drugs. After LDH, the expressions of TS decreased to 12.06%, OPRT increased by 4.17-fold, and DPD did not change (1.03-fold). This transformations will induce susceptibility to 5-FU. LDH may be a useful enhancer of chemotherapy drugs for squamous cell carcinoma.

Predicting difficulty in extending the ileal pouch to the anus in restorative proctocolectomy: investigation of a simple predictive method using computed tomography.

AIM: This study aimed to assess the ability of preoperative axial computed tomography (CT) to predict surgical difficulty in bringing the ileal pouch to the level of the anus during restorative proctocolectomy (RPC). METHOD: Patients who underwent RPC with an ileal pouch-anal anastomosis (or ileal pouch-anal canal anastomosis) in our institution between January 2008 and April 2014 were enrolled. The patients were divided into two groups, including those in whom CT indicated potential difficulty in extending the pouch downwards (extension difficult (ED) group) and patients with no CT evidence of potential difficulty (normal group). The groups were compared for clinical factors and the thickness of the slices of CT showing the root of the superior mesenteric artery, the point of communication of the ileocaecal artery with the marginal artery (tICA) and the anal verge (AV). Receiver-operating characteristic analysis was performed, and a cut-off value was calculated for predicting the degree of difficulty in bringing the ileal pouch down to the anal canal. RESULTS: Thirty-four patients were entered in the study. The ED group included significantly taller patients and more with familial adenomatous polyposis than the normal group. The distance between tICA and AV was significantly longer in the ED group, with a cut-off of 21 cm giving a sensitivity of 100% and a specificity of 83.3%. CONCLUSION: The distance between tICA and AV measured by axial CT can be a useful predictor for the difficulty in bringing the ileal pouch down to the anus during RPC.

Impact of hospital volume on risk-adjusted mortality following oesophagectomy in Japan.

BACKGROUND: Previous studies have reported that patients undergoing oesophagectomy in high-volume hospitals experience lower mortality rates. However, there has been ongoing discussion regarding the validity of evidence for this association. The purpose of this study was to investigate the relationship between hospital volume and risk-adjusted mortality following oesophagectomy in Japan, using a nationwide web-based database. METHODS: The study included patients registered in the database as having undergone oesophagectomy with reconstruction between 2011 and 2013. Outcome measures were 30-day and operative mortality rates. Logistic regression analysis was used to adjust for hospital volume, surgeon volume and risk factors for mortality after oesophagectomy. RESULTS: A total of 16 556 oesophagectomies at 988 hospitals were included; the overall unadjusted 30-day and operative mortality rates were 1·1 and 3·0 per cent respectively. The unadjusted operative mortality rate in hospitals performing fewer than ten procedures per year (5·1 per cent) was more than three times higher than that in hospitals conducting 30 or more procedures annually (1·5 per cent). Multivariable models indicated that hospital volume had a significant effect on 30-day (odds ratio 0·88 per 10-patient increase; P = 0·012) and operative (odds ratio 0·86 per 10-patient increase; P < 0·001) mortality. CONCLUSION: In Japan, high-volume hospitals had lower risk-adjusted 30-day and operative mortality rates following oesophagectomy compared with low-volume hospitals.

Adenovirus-mediated FIR demonstrated TP53-independent cell-killing effect and enhanced antitumor activity of carbon-ion beams.

Combination therapy of carbon-ion beam with the far upstream element-binding protein (FBP)-interacting repressor, FIR, which interferes with DNA damage repair proteins, was proposed as an approach for esophageal cancer treatment with low side effects regardless of TP53 status. In vivo therapeutic antitumor efficacy of replication-defective adenovirus (E1 and E3 deleted adenovirus serotype 5) encoding human FIR cDNA (Ad-FIR) was demonstrated in the tumor xenograft model of human esophageal squamous cancer cells, TE-2. Bleomycin (BLM) is an anticancer agent that introduces DNA breaks. The authors reported that Ad-FIR involved in the BLM-induced DNA damage repair response and thus applicable for other DNA damaging agents. To examine the effect of Ad-FIR on DNA damage repair, BLM, X-ray and carbon-ion irradiation were used as DNA damaging agents. The biological effects of high linear energy transfer (LET) radiotherapy used with carbon-ion irradiation are more expansive than low-LET conventional radiotherapy, such as X-rays or γ rays. High LET radiotherapy is suitable for the local control of tumors because of its high relative biological effectiveness. Ad-FIR enhanced BLM-induced DNA damage indicated by γH2AX in vitro. BLM treatment increased endogenous nuclear FIR expression in TE-2 cells, and P27Kip1 expression was suppressed by TP53 siRNA and BLM treatment. Further, Ad-FIRΔexon2, a dominant-negative form of FIR that lacks exon2 transcriptional repression domain, decreased Ku86 expression. The combination of Ad-FIR and BLM in TP53 siRNA increased DNA damage. Additionally, Ad-FIR showed synergistic cell toxicity with X-ray in vitro and significantly increased the antitumor efficacy of carbon-ion irradiation in the xenograft mouse model of TE-2 cells (P=0.03, Mann-Whitney's U-test) and was synergistic with the sensitization enhancement ratio (SER) value of 1.15. Therefore, Ad-FIR increased the cell-killing activity of the carbon-ion beam that avoids late-phase severe adverse effects independently of the TP53 status in vitro. Our findings indicated the feasibility of the combination of Ad-FIR with DNA damaging agents for future esophageal cancer treatment.

Objective assessment in digital images of skin erythema caused by radiotherapy.

PURPOSE: Skin toxicity caused by radiotherapy has been visually classified into discrete grades. The present study proposes an objective and continuous assessment method of skin erythema in digital images taken under arbitrary lighting conditions, which is the case for most clinical environments. The purpose of this paper is to show the feasibility of the proposed method. METHODS: Clinical data were gathered from six patients who received carbon beam therapy for lung cancer. Skin condition was recorded using an ordinary compact digital camera under unfixed lighting conditions; a laser Doppler flowmeter was used to measure blood flow in the skin. The photos and measurements were taken at 3 h, 30, and 90 days after irradiation. Images were decomposed into hemoglobin and melanin colors using independent component analysis. Pixel values in hemoglobin color images were compared with skin dose and skin blood flow. The uncertainty of the practical photographic method was also studied in nonclinical experiments. RESULTS: The clinical data showed good linearity between skin dose, skin blood flow, and pixel value in the hemoglobin color images; their correlation coefficients were larger than 0.7. It was deduced from the nonclinical that the uncertainty due to the proposed method with photography was 15%; such an uncertainty was not critical for assessment of skin erythema in practical use. CONCLUSIONS: Feasibility of the proposed method for assessment of skin erythema using digital images was demonstrated. The numerical relationship obtained helped to predict skin erythema by artificial processing of skin images. Although the proposed method using photographs taken under unfixed lighting conditions increased the uncertainty of skin information in the images, it was shown to be powerful for the assessment of skin conditions because of its flexibility and adaptability.

Uric acid, indoxyl sulfate, and methylguanidine activate bulbospinal neurons in the RVLM via their specific transporters and by producing oxidative stress.

Patients with chronic renal failure often have hypertension, but the cause of hypertension, other than an excess of body fluid, is not well known. We hypothesized that the bulbospinal neurons in the rostral ventrolateral medulla (RVLM) are stimulated by uremic toxins in patients with chronic renal failure. To investigate whether RVLM neurons are sensitive to uremic toxins, such as uric acid, indoxyl sulfate, or methylguanidine, we examined changes in the membrane potentials (MPs) of bulbospinal RVLM neurons of Wister rats using the whole-cell patch-clamp technique during superfusion with these toxins. A brainstem-spinal cord preparation that preserved the sympathetic nervous system was used for the experiments. During uric acid, indoxyl sulfate, or methylguanidine superfusion, almost all the RVLM neurons were depolarized. To examine the transporters for these toxins on RVLM neurons, histological examinations were performed. The uric acid-, indoxyl sulfate-, and methylguanidine-depolarized RVLM neurons showed the presence of urate transporter 1 (URAT 1), organic anion transporter (OAT)1 or OAT3, and organic cation transporter (OCT)3, respectively. Furthermore, the toxin-induced activities of the RVLM neurons were suppressed by the addition of an anti-oxidation drug (VAS2870, an NAD(P)H oxidase inhibitor), and a histological examination revealed the presence of NAD(P)H oxidase (nox)2 and nox4 in these RVLM neurons. The present results show that uric acid, indoxyl sulfate, and methylguanidine directly stimulate bulbospinal RVLM neurons via specific transporters on these neurons and by producing oxidative stress. These uremic toxins may cause hypertension by activating RVLM neurons.

Pathologic findings of renal biopsy were a helpful diagnostic clue of stenosis of the iliac segment proximal to the transplant renal artery: a case report.

Common iliac artery stenosis after renal transplantation is a rare complication; it can occur in the course of hypertension and renal dysfunction. We report a case of suspected renal allograft rejection with iliac artery stenosis proximal to a transplanted kidney. A 52-year-old man with a history of cadaveric kidney transplantation 26 years previously underwent a second cadaveric kidney transplantation in the left iliac fossa because of graft failure 3 years before. In June 2012, the patient had progressive renal dysfunction. In July, a percutaneous needle biopsy was taken, and it showed no rejection; however, his renal function continued to get worse through September. A percutaneous allograft renal biopsy was performed under ultrasound guidance and showed hyperplasia of the juxtaglomerular apparatus and renin granules. Magnetic resonance angiography was used to evaluate the arteries in the pelvis and showed left common iliac artery stenosis, and a stent was placed. After percutaneous intervention, the patient's ankle brachial pressure index was within the normal range and the allograft function had improved.

MicroRNA-133a regulates the mRNAs of two invadopodia-related proteins, FSCN1 and MMP14, in esophageal cancer.

BACKGROUND: FSCN1 and matrix metalloproteinase 14 (MMP14) are both invadopodia-related proteins. We herein elucidate the tumourigenicity of these proteins and identify novel therapeutic agents in esophageal squamous cell carcinoma (ESCC). METHODS: FSCN1 and MMP14 were evaluated by immunohistochemistry and quantitative PCR, and microRNA (miR)-133a was also evaluated by PCR in surgical ESCC specimens. The roles of FSCN1, MMP14 and miR-133a were established in ESCC cells. RESULTS: The expression of FSCN1 or MMP14 was an independent poor prognostic factor according to a multivariate analysis of immunohistochemistry, and their co-expression correlated with the poorest overall survival (OS) out of all the examined factors. Additionally, their mRNAs significantly correlated and both inversely correlated with miR-133a in surgical specimens. Transfection of a miR-133a mimic decreased the mRNA and protein levels of both FSCN1 and MMP14 in ESCC cells. The knockdown of FSCN1 or MMP14 and transfection of a miR-133a mimic inhibited the proliferation and invasion of ESCC cells. Patients with a lower miR-133a expression have a significantly poorer OS than those with a higher expression. CONCLUSION: The combined expression of FSCN1 and MMP14 is associated with a poor prognosis, and miR-133a, which regulates their mRNAs, can serve as a strong tumour suppressor of ESCC.

Serum microRNA expression profile: miR-1246 as a novel diagnostic and prognostic biomarker for oesophageal squamous cell carcinoma.

BACKGROUND: Recent studies have demonstrated that microRNAs (miRNAs) are stably detectable in blood and can serve as useful biomarkers for cancer. METHODS: We performed an miRNA array using serum samples obtained from oesophageal squamous cell carcinoma (ESCC) patients or healthy controls. MiR-1246 was the most markedly elevated in ESCC patients. Therefore, miR-1246 was selected as a candidate for further analysis. The serum miR-1246 level in 46 healthy controls and 101 ESCC patients was evaluated and compared among various clinicopathological characteristics. MiR-1246 expressions in tissue, exosomal, and cellular samples were also examined. RESULTS: Serum miR-1246 alone yielded an receiver-operating characteristic curve area of 0.754, with 71.3% sensitivity and 73.9% specificity for distinguishing ESCC patients from healthy controls. Serum miR-1246 was significantly correlated with the TNM stage and showed to be the strongest independent risk factor for poor survival (HR, 4.032; P=0.017). Unlike the tendency shown in previous reports, miR-1246 was not upregulated in ESCC tissue samples. Furthermore, exosomal miR-1246 did not reflect the abundance in the cell of origin. CONCLUSION: These data support our contention that serum miR-1246 has strong potential as a novel diagnostic and prognostic biomarker in ESCC, and its releasing mechanism is selective and independent of tissue miRNA abundance.

[Evaluation of thoracography for secondary pneumothorax in elderly people].

The thoracoscopic surgery for patient with pneumothorax has been considered to be safe and easy. In recent years, there is a growing number of secondary pneumothorax due to advanced pulmonary emphysema in elderly patients. To confirm the existence of adhesion and the site of air leakage are important prior to surgery. In our institution, thoracography was performed before surgery in 9 cases of emphysema and secondary pneumothorax over 60 years old patients. The mean age was 72.2 years old and all patients were male. Air leakage and its site could be identified in 6 cases by thoracography. In the remaining 3 cases, adhesion sites were identified. There were no complications in all cases. The operation time was 117 minutes, and blood loss was 9.9 ml in average. The mean postoperative drainage period was 1.6 days and total hospital stay was 5.9 days. We conclude that the thoracoscopic surgery can be performed more safely by obtaining information of thoracic cavity using thoracography before surgery.

A case of Goodpasture syndrome positive for anti-GBM antibody and MPO-ANCA complicated by a variety of serious infections.

A 62-year-old female was admitted to our hospital for investigation of acute progressive renal insufficiency and a systemic inflammatory reaction, despite treatment with several antibiotics. Laboratory data revealed severe renal insufficiency and positive titers for the myeloperoxidase anti-neutrophil cytoplasmic and anti-glomerular basement membrane antibodies. The deterioration of her general status did not allow us to perform the renal biopsy. Although corticosteroid therapy, hemodialysis, and plasma exchange were concomitantly initiated, pulmonary hemorrhage occurred several days after admission. Mechanical ventilation support was provided and continuous hemodiafiltration was carried out, following which the respiratory failure improved immediately. However, she developed clinical depression and suicidal behavior under the intensive therapy. Therefore, plasma exchange was discontinued and corticosteroid was tapered as quickly as possible. Four months after admission, platelet transfusion and short-term mechanical ventilation support improved the pulmonary hemorrhage; however, her mental status deteriorated despite psychiatric consultation and treatment with a tranquilizer. Thereafter, severe and serious systemic infection due to various pathogens including Staphylococcus aureus, Cytomegalovirus, Pneumocystis jiroveci, Pseudomonas aeruginosa, and Bacteroides recurred, and she died from systemic invasive aspergillosis (IA). We suspected severe immunosuppression caused by various factors, such as predonisolone administration, chronic renal failure on maintenance hemodialysis, depression, and malnutrition due to chronic inflammation and granulocytopenia as a side effect of ganciclovir. When treating rapidly progressive glomerulonephritis, immunosuppressive status should be carefully monitored regarding not only the dosage of therapeutic regimen but also the mental health status and nutrition of the patient.

Bone marrow mononuclear cells versus G-CSF-mobilized peripheral blood mononuclear cells for treatment of lower limb ASO: pooled analysis for long-term prognosis.

In this study, we report the comparative result of long-term clinical prognoses for patients with no-option critical limb ischemia (CLI) caused by arteriosclerosis obliterans, who are implanted with autologous bone marrow mononuclear cells (BMMNC; n=74) or G-CSF-mobilized (M)-PBMNC (n=111), as no information is available on how the two treatments compare in terms of long-term prognosis, such as survival or amputation. We performed pooled analysis using data from two previous cohort studies. All patients had disease of Fontaine classification III or IV. The endpoints were OS and amputation-free survival (AFS). After adjustment for history of dialysis and Fontaine classification, there was no significant difference between the two treatments with respect to OS (hazard ratio (HR)=1.49; 95% confidence interval (CI)=0.74-3.03, P=0.26) or AFS (HR=0.96; 95% CI=0.61-1.51, P=0.87). The negative prognostic factors affecting OS or AFS were the small number of CD34-positive cells collected, history of dialysis, Fontaine classification, male sex and older age. These results suggest that there was no significant difference in long-term prognosis between patients treated with BMMNC and those treated with M-PBMNC. The number of CD34-positive cells collected was an important prognostic factor for amputation and death.

Pathophysiology of vascular calcification: Pivotal role of cellular senescence in vascular smooth muscle cells.

The accumulation of senescent cells within tissues can potentially lead to biological dysfunction and manifestation of disease associated with ageing. The majority of senescent cells display a commonly altered secretome similar to a wound healing response (termed the senescence-associated secretory phenotype or SASP), which could have deleterious implications on the tissue microenvironment. However, senescent cells also appear to have a cell-type (or even cell-strain) exclusive senescent phenotype (CESP), an area of research that is underexplored. One such CESP is the pro-calcificatory phenotype recently reported in senescent vascular smooth muscle cells (VSMCs). Senescent VSMCs have been shown to overexpress genes and proteins (including RUNX-2, alkaline phosphatase (ALP), type I collagen and BMP-2) associated with osteoblasts, leading to partial osteoblastic transdifferentiation. As such, it has been suggested that senescent VSMCs contribute to cardiovascular dysfunction through induction of vascular calcification. This review discusses recent findings on VSMC senescence and their potential role in the pathophysiology of vascular calcification.

Histological diversity in basaloid squamous cell carcinoma of the esophagus.

Basaloid squamous cell carcinoma of the esophagus (BSCCE) is a distinct variant of esophageal cancer. This study investigated histopathological variations of BSCCE. Thirty-eight surgical and two endoscopically resected specimens of BSCCE were examined. Histological features were classified into five components: solid nest (SN), microcyst and/or trabecular nest (MT), ductal differentiation (DD), cribriform pattern (CP), and an invasive squamous cell carcinoma (SCC) component. The immunohistochemical phenotypes of each component were examined using antibodies against cytokeratin (CK) 7, CK14, and alpha smooth muscle actin (SMA). SN, MT, DD, CP, and SCC were present in 95.0, 97.5, 27.5, 32.5, and 82.5% of the cases, respectively, and combinations of SN & MT, SN & DD, SN, MT & DD, SN, MT & CP, and SN, MT, DD & CP were found in 50.0, 2.5, 10.0, 17.5, and 15.0%, respectively. All the intraepithelial lesions observed in 18 (45.0%) cases were SCC. Immunoreactivity for CK7, CK14, and SMA was seen in 10.5, 86.8, and 18.4% of SN; 30.8, 97.4, and 38.5% of MT; 54.5, 100.0, and 54.5% of DD; 7.7, 76.9, and 23.1% of CP; and 6.1, 97.0, and 0.0% of SCC, respectively. CK14 immunoreactivity was seen in the periphery of most of the SN component. CK7, CK14, and SMA immunoreactivity was seen in the inner layer, all layers, and the outer layer of DD, respectively. MT and CP showed partial peripheral positivity for CK14 and SMA in microcystic, trabecular, and cribriform-like pseudoglandular structures. BSCCE demonstrates various histopathological and immunohistochemical features including a ductal and cribriform growth pattern.

Ilizarov technique for correction of the Shepherd's crook deformity: a report of two cases.

We report 2 patients with fibrous dysplasia who underwent correction, using the Ilizarov technique, of Shepherd's crook deformities and pathological fractures of the left femurs. A 12-year-old boy underwent an opening wedge osteotomy and a 48-degree gradual correction, whereas a 43-year-old woman underwent a 34-degree acute correction without osteotomy at the fracture site. Both patients could initiate early weight bearing. Final leg function was excellent and alignment was maintained. No complications were encountered. Both patients had no difficulty sleeping and no major complaints about the Ilizarov technique. It is more important to achieve accurate alignment than resection of the lesion. The Ilizarov technique is effective for treating the Shepherd's crook deformity in patients with fibrous dysplasia.

The Bcr-Abl kinase inhibitor INNO-406 induces autophagy and different modes of cell death execution in Bcr-Abl-positive leukemias.

Bcr-Abl tyrosine kinase (TK) inhibitors are promising therapeutic agents for Bcr-Abl-positive (Bcr-Abl(+)) leukemias. Although they are known to promote caspase-mediated apoptosis, it remains unclear whether caspase-independent cell death-inducing mechanisms are also triggered. Here we demonstrated that INNO-406, a second-generation Bcr-Abl TK inhibitor, induces programmed cell death (PCD) in chronic myelogenous leukemia (CML) cell lines through both caspase-mediated and caspase-independent pathways. The latter pathways include caspase-independent apoptosis (CIA) and necrosis-like cell death (CIND), and the cell lines varied regarding which mechanism was elicited upon INNO-406 treatment. We also observed that the propensity toward CIA or CIND in cells was strongly associated with cellular dependency on apoptosome-mediated caspase activity. Cells that undergo CIND have a high apoptosome activity potential whereas cells that undergo CIA tend to have a lower potential. Moreover, we found that INNO-406 promotes autophagy. When autophagy was inhibited with chloroquine or gene knockdown of beclin1 by shRNA, INNO-406-induced cell death was enhanced, which indicates that the autophagic response of the tumor cells is protective. These findings suggest new insights into the biology and therapy of Bcr-Abl(+) leukemias.